PROJECT SUMMARY Even though several genes, mutations and genetic variants have been identified to have key roles in Alzheimer?s disease (AD), these findings have not yet been translated into effective treatments. In order to increase our chances of identifying successful drug targets it is critical to identify new genetic causes and risk factors of AD. Our long-term goal is therefore to use genetic approaches to identify therapeutic targets for the prevention, onset delay or treatment of AD. Taking advantage of the unique genetic background of an understudied population, this application?s main objective is to identify novel genes and genetic factors involved in AD. The proposed research focuses on the Portuguese population because of its unique genetic profile; although quite homogeneous and mainly European, the genetic profile of this population is enriched by contributions from North and Sub-Saharan African as well as from Sephardic Jewish populations. Moreover, the high number of early-onset cases and of families with several generations affected by AD, indicates a strong genetic contribution in the Portuguese population, despite the low frequency of known AD mutations. Our preliminary studies also show that the frequency of risk variants differs substantially from other populations. Specifically, common and rare genetic risk variants associated with AD will be identified by using a combination of whole genome genotyping, genome-wide association study (GWAS) analyses, and imputation in a Portuguese sample set. These data will then be used to perform a multi-ethnic GWAS by incorporating publicly available data from other populations, allowing the increase of diversity and statistical power of our GWAS. In addition, the genetic characterization of familial and early-onset AD cases in the Portuguese population will be carried out by performing whole genome sequencing. Analyses in multiplex families lacking coding mutations in the known AD-causing genes and in a sub-group of early-onset AD cases will allow the identification of variants with strong effects in disease. Together these data will allow the identification of common, rare and very rare variants with different effects in AD. The proposed research will also allow the comparison and integration with data generated from worldwide populations leading to i) a substantial increase in diversity and statistical power of the currently available genetic analyses in AD, and ii) the development of a publicly available database and interactive map (accessible via Alzforum) reporting the different genetic contributions to AD across populations.